Gene transfer to the central nervous system by transplantation of cerebral endothelial cells

Evaluation of Tet-on system to avoid transgene down-regulation in ex vivo gene transfer to the CNS

“…The observed down-regulation is in line with previous ex vivo studies. These studies have shown gradual decline of transgene expression from retroviral vectors in cerebral endothelial cells, 3 primary astrocytes 2,4 or fibroblast 26 despite longterm graft survival. The present data show that plasmid vector-mediated gene expression, similar to retroviral vectors, is down-regulated in vivo.…”

“…[2][3][4] Current approaches to ex vivo gene transfer frequently employ retroviral vectors directing transgene expression typically from the internal LTR promoter 3 or the heterologous CMV promoter, 2 lation has occurred independently of promoter. Consequently, exploring alternative promoters and vector types may efficiently address the expression stability issue.…”

Increased in vitro and in vivo transgene expression levels mediated through cis‐acting elements

“…Though in vitro expression from engineered HiB5 cells was stable over prolonged periods of time, transgene expression from plasmid vectors was almost completely abolished shortly after transplantation. The phenomenon of in vivo down-regulation after ex vivo gene transfer has been described in several contexts independent of whether the vector system employed is a viral or non-viral one [2][3][4][5][6][7]. However, improving current vector designs through alternative combinations of genetic cis-acting elements may result in more stable in vivo transgene expression.…”

Endothelial Cell Transplantation for Gene Therapy in Experimental Gliomas

“…In a previous study, Lal et al (5) reported that implanted allogeneic immortalized endothelial cells expressing the LacZ gene survive, proliferate, and take part in the vascularization induced in gliomas after intracranial and subcutaneous inoculation. Furthermore, Quinonero et al (11) found that syngeneic immortalized BECs implanted into normal brain were associated with vascular structures but did not localize within the host endothelium. Consistent with this finding, we detected the transduced endothelial cells closely associated with the vascular wall, but they rarely intercalated within the tumor endothelium.…”